TY - JOUR
T1 - Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia
AU - Khera, Amit V.
AU - Won, Hong Hee
AU - Peloso, Gina M.
AU - Lawson, Kim S.
AU - Bartz, Traci M.
AU - Deng, Xuan
AU - van Leeuwen, Elisabeth M.
AU - Natarajan, Pradeep
AU - Emdin, Connor A.
AU - Bick, Alexander G.
AU - Morrison, Alanna C.
AU - Brody, Jennifer A.
AU - Gupta, Namrata
AU - Nomura, Akihiro
AU - Kessler, Thorsten
AU - Duga, Stefano
AU - Bis, Joshua C.
AU - van Duijn, Cornelia M.
AU - Cupples, L. Adrienne
AU - Psaty, Bruce
AU - Rader, Daniel J.
AU - Danesh, John
AU - Schunkert, Heribert
AU - McPherson, Ruth
AU - Farrall, Martin
AU - Watkins, Hugh
AU - Lander, Eric
AU - Wilson, James G.
AU - Correa, Adolfo
AU - Boerwinkle, Eric
AU - Merlini, Piera Angelica
AU - Ardissino, Diego
AU - Saleheen, Danish
AU - Gabriel, Stacey
AU - Kathiresan, Sekar
PY - 2016/6/7
Y1 - 2016/6/7
N2 - Background Approximately 7% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by a single LDL cholesterol measurement. Objectives This study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level. Methods Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database. Results Among 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7%) had LDL cholesterol ≥190 mg/dl; of these, only 24 (1.7%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol ≥190 mg/dl and an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers. Conclusions Among participants with LDL cholesterol ≥190 mg/dl, gene sequencing identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD.
AB - Background Approximately 7% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by a single LDL cholesterol measurement. Objectives This study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level. Methods Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database. Results Among 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7%) had LDL cholesterol ≥190 mg/dl; of these, only 24 (1.7%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol ≥190 mg/dl and an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers. Conclusions Among participants with LDL cholesterol ≥190 mg/dl, gene sequencing identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD.
KW - coronary artery disease
KW - gene sequencing
KW - genetics
KW - low-density lipoprotein cholesterol
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U2 - 10.1016/j.jacc.2016.03.520
DO - 10.1016/j.jacc.2016.03.520
M3 - Article
AN - SCOPUS:84969596203
VL - 67
SP - 2578
EP - 2589
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
SN - 0735-1097
IS - 22
ER -